Polymorphs of an epothilone analog

ABSTRACT

There are provided in accordance with the present invention two crystalline polymorphs, designated Form A and Form B, respectively, as well as mixtures thereof, of an epothilone analog represented by the formula  
                 
 
     Also provided are methods of forming the novel polymorphs, therapeutic methods utilizing them and pharmaceutical dosage forms containing them.

FIELD OF THE INVENTION

[0001] The present invention relates to crystalline polymorphic forms ofa highly potent epothilone analog that is characterized by enhancedproperties.

BACKGROUND OF THE INVENTION

[0002] Epothilones are macrolide compounds that find utility in thepharmaceutical field. For example, Epothilones A and B having thestructures:

[0003] may be found to exert microtubule-stabilizing effects similar topaclitaxel (TAXOL®) and hence cytotoxic activity against rapidlyproliferating cells, such as, tumor cells or other hyperproliferativecellular disease, see Hofle, G., et al., Angew. Chem. Int. Ed. Engl.,Vol. 35, No.13/14, 1567-1569 (1996); W093/10121 published May 27, 1993;and WO97/19086 published May 29, 1997.

[0004] Various epothilone analogs have been synthesized and may be usedto treat a variety of cancers and other abnormal proliferative diseases.Such analogs are disclosed in Hofle et al., Id.; Nicolaou, K. C., etal., Angew Chem. Int. Ed. Engl. Vol. 36, No. 19, 2097-2103 (1997); andSu, D.-S., et al., Angew Chem. Int. Ed. Engl., Vol. 36, No. 19,2093-2097 (1997).

[0005] A particularly advantageous epothilone analog that has been foundto have advantageous activity is [1S-[1R*,3R*(E),7R*, 10S* ,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.In accordance with the present invention, two crystal forms of thesubject epothilone analog are provided. These polymorphs, which havebeen designated as Forms A and B, respectively, are novel crystal formsand are identified hereinbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006]FIG. 1 is a powder x-ray diffraction pattern (CuKα λ=1.5406 Å atroom temperature) of Form A of the subject epothilone analog.

[0007]FIG. 2 is a powder x-ray diffraction pattern of Form B (Cu Kαλ=1.5406 Å at room temperature) of the subject epothilone analog.

[0008]FIG. 3 is a powder x-ray diffraction pattern of a mixture of FormsA and B (Cu Kα λ=1.5406 Å at room temperature) of the subject epothiloneanalog.

[0009]FIG. 4 is a comparison of the simulated and actual powder x-raydiffraction patterns of Forms A and B of the subject epothilone analog.

[0010]FIG. 5 is a Raman spectrum of Form A of the subject epothiloneanalog.

[0011]FIG. 6 is a Raman spectrum of Form B of the subject epothiloneanalog.

[0012]FIG. 7 is a Raman spectrum of a mixture of Forms A and B of thesubject epothilone analog.

[0013]FIG. 8 depicts the solid state conformation in Form A of thesubject epothilone analog.

[0014]FIG. 9 depicts the solid state conformation in Form B of thesubject epothilone analog.

SUMMARY OF THE INVENTION

[0015] In accordance with the present invention, there are provided twocrystalline polymorphs of the epothilone analog represented by formula1.

[0016] One of these polymorphs, designated Form A, has been found tohave particularly advantageous properties. The present invention isdirected to crystalline polymorphs Form A and Form B as well as mixturesthereof. The present invention further pertains to the use of thesecrystalline forms in the treatment of cancers and other proliferatingdiseases and pharmaceutical formulations containing them.

DETAILED DESCRIPTION OF THE INVENTION

[0017] In accordance with the present invention, there are providedpolymorphs of an epothilone analog represented by formula I below

[0018] The epothilone analog represented by formula I chemically is[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.This analog and the preparation thereof are described in U.S. patentapplication Ser. No. 09/170,582, filed Oct. 13, 1998, the disclosure ofwhich is incorporated herein by reference. The polymorphs of the analogrepresented by formula I above are microtubule-stabilizing agents. Theyare thus useful in the treatment of a variety of cancers and otherproliferative diseases including, but not limited to, the following;

[0019] carcinoma, including that of the bladder, breast, colon, kidney,liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin,including squamous cell carcinoma;

[0020] hematopoietic tumors of lymphoid lineage, including leukemia,acute lymphocytic leukemia, acute lymphoblastic leukemia, B-celllymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma,hairy cell lymphoma and Burketts lymphoma;

[0021] hematopoietic tumors of myeloid lineage, including acute andchronic myelogenous leukemias and promyelocytic leukemia;

[0022] tumors of mesenchymal origin, including fibrosarcoma andrhabdomyoscarcoma;

[0023] other tumors, including melanoma, seminoma, teratocarcinoma,neuroblastoma and glioma;

[0024] tumors of the central and peripheral nervous system, includingastrocytoma, neuroblastoma, glioma, and schwannomas;

[0025] tumors of mesenchymal origin, including fibrosarcoma,rhabdomyoscaroma, and osteosarcoma; and

[0026] other tumors, including melanoma, xeroderma pigmentosum,keratoacanthoma, seminoma, thyroid follicular cancer andteratocarcinoma.

[0027] The subject polymorphs will also inhibit angiogenesis, therebyaffecting the growth of tumors and providing treatment of tumors andtumor-related disorders. Such anti-angiogenesis properties will also beuseful in the treatment of other conditions responsive toanti-angiogenesis agents including, but not limited to, certain forms ofblindness related to retinal vascularization, arthritis, especiallyinflammatory arthritis, multiple sclerosis, restinosis and psoriasis.

[0028] The polymorphs of the analog represented by formula I will induceor inhibit apoptosis, a physiological cell death process critical fornormal development and homeostasis. Alterations of apoptotic pathwayscontribute to the pathogenesis of a variety of human diseases. Thesubject polymorphs, as modulators of apoptosis, will be useful in thetreatment of a variety of human diseases with aberrations in apoptosisincluding, but not limited to, cancer and precancerous lesions, immuneresponse related diseases, viral infections, degenerative diseases ofthe musculoskeletal system and kidney disease.

[0029] Without wishing to be bound to any mechanism or morphology, thesuch crystalline forms of the epothilone analog represented by formula Imay also be used to treat conditions other than cancer or otherproliferative diseases. Such conditions include, but are not limited toviral infections such as herpesvirus, poxvirus, Epstein-Barr virus,Sindbis virus and adenovirus; autoimmune diseases such as systemic lupuserythematosus, immune mediated glomerulonephritis, rheumatoid arthritis,psoriasis, inflammatory bowel diseases and autoimmune diabetes mellitus;neurodegenerative disorders such as Alzheimer's disease, AIDS-relateddementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitispigmentosa, spinal muscular atrophy and cerebellar degeneration; AIDS;myelodysplastic syndromes; aplastic anemia; ischemic injury associatedmyocardial infarctions; stroke and reperfusion injury; restenosis;arrhythmia; atherosclerosis; toxin-induced or alcohol induced liverdiseases; hematological diseases such as chronic anemia and aplasticanemia; degenerative diseases of the musculoskeletal system such asosteoporosis and arthritis; aspirin-sensitive rhinosinusitis; cysticfibrosis; multiple sclerosis; kidney diseases; and cancer pain.

[0030] The effective amount of the subject polymorphs, particularly FormA, may be determined by one of ordinary skill in the art, and includesexemplary dosage amounts for a human of from about 0.05 to 200mg/kg/day, which may be administered in a single dose or in the form ofindividual divided doses, such as from 1 to 4 times per day. Preferably,the subject polymorphs are administered in a dosage of less than 100mg/kg/day, in a single dose or in 2 to 4 divided doses. It will beunderstood that the specific dose level and frequency of dosage for anyparticular subject may be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the species,age, body weight, general health, sex and diet of the subject, the modeand time of administration, rate of excretion, drug combination, andseverity of the particular condition. The subject polymorphs arepreferably administered parenterally, however, other routes ofadministration are contemplated herein as are recognized by those skillin the oncology arts. Preferred subjects for treatment include animals,most preferably mammalian species such as humans, and domestic animalssuch as dogs, cats and the like, subject to the aforementioneddisorders.

[0031] The preparation of the epothilone analogs represented by formulaI described in U.S. patent application Ser. No. 09/170,582 produced thesubject epothilone analog as an oil that can be chromatographed andpurified to yield an amorphous powder. A preferred preparation isdescribed in a continuing application under Ser. No. 09/528,526 filed onMar. 20, 2000, the disclosure of which is incorporated herein byreference. In this preparation, as pertains to the analogs representedby formula I, epothilone B is reacted with an azide donor agent and abuffering agent in the presence of a palladium catalyst and a reducingagent to form an intermediate represented by the formula

[0032] A macrolactamization reaction is then carried out on theintermediate to form the analog represented by formula I. It has nowbeen found that this analog, in its crystalline form, consists of amixture of Forms A and B as fully described herein. The amorphous formof the epothilone analog represented by formula I can be taken up in asuitable solvent, preferably a mixed solvent such as ethylacetate/dichloromethane/triethylamine, purified such as by silica gelpad filtration, and crystallized by cooling to a temperature of about 5°C. to form a crystalline material that is a mixture of Form A and FormB. The purification step using a solvent mixture containing a componentsuch as dichloromethane removes residual solvents from the synthesisthat could interfere with the crystallization process.

[0033] Generally, taking the purified material in a limited amount ofethyl acetate and heating the resultant slurry to about 75-80° C. willcause the formation of Form A. By limited amount is meant from about 8to 16 mL, preferably from about 8 to 12 mL, of ethyl acetate per gram ofpurified material. As the solution is heated, a thin slurry forms whichhas been found to be predominately Form B. At about 75° C. the slurryundergoes a material thickening which has been found to be the formationof Form A. The slurry is held at about 75-80° C. for about an hour toassure completion of the formation of Form A at which time cyclohexaneis added to the slurry in a ratio to ethyl acetate of from about 1:2 to2:2, preferably about 1:2, and the mixture is allowed to cool to ambienttemperature at which it is maintained with stirring for a period of fromabout 12 to 96 hours. The mixture is then cooled to about 5° C. overabout two hours after which the crystals of Form A of the subjectepothilone analog are recovered. Form A is afforded in good yield andpurity.

[0034] Alternate procedures for the preparation of Form A involve theaddition of seed crystals. In the descriptions that follow, seedcrystals of Form A were used, but seed crystals of Form B, or mixturesthereof can be used as well. In one such procedure, the purifiedmaterial is taken up in a limited amount of ethyl acetate as describedabove and heated to about 75° C., seed crystals are added and themixture maintained for about 30 minutes. An amount of cyclohexane asdescribed above is then added dropwise maintaining the temperature atabout 70° C. The mixture is thereafter cooled to 20° C. and held withstirring for 18 hours after which it is cooled to 5° C. and the whitecrystals of Form A recovered by physical separation, e.g. filtration.

[0035] In a second procedure, the initial solution of material in ethylacetate is heated to 75° C. for at least an hour until a solution isproduced. The solution is cooled to about 50° C. over the course ofabout two hours adding seed crystals of Form A when the temperaturereaches about 60° C. Crystals begin to appear at about 55° C. Thetemperature is again reduced to about 20° C. over a further two hoursduring one hour of which an amount of cyclohexane as described above isadded dropwise. The final slurry is further cooled over two hours to−10° C. and held at that temperature for an additional hour. The slurryis then filtered to afford white crystals of Form A.

[0036] In a further alternate procedure, the material is taken up in alarger amount, i.e. at least about 40 mL/g of ethyl acetate and theresultant slurry heated to about 80 ° C. until a solution is formedwhich is then cooled to about 70° C. over the course of about one hour.Seed crystals of Form A are added when the solution temperature reachesabout 70° C. The temperature is then reduced to about 30° C. over afurther three hours. Crystals begin to appear at about 65° C. Thetemperature is reduced to −10° C. over an additional three hours duringa thirty minute period thereof a quantity of cyclohexane as describedabove is added dropwise. The temperature is maintained at −10° C. for afurther hour. The final slurry is filtered to afford white crystals ofForm A. The yield and purity of Form A by these procedures is consideredvery good.

[0037] Form B of the subject epothilone analogs represented by Formula Iabove is obtained by forming a slurry of the crude material in a largerquantity of ethyl acetate, i.e. from about 40 to 50 mL per g., andheating at 70° C. to 80° C. for an hour to form a solution which is thenheld at temperature for about thirty minutes. The solution is cooled toabout 30° C. over the course of about two hours, crystals beginning toappear at about 38° C. The temperature is further reduced to about −10°C. over one hour during which a quantity of cyclohexane as describedabove is added dropwise over a period of thirty minutes. The finalslurry is held at −10° C. over a further two hours and filtered toafford white crystals of Form B.

[0038] In an alternative preparation to that above, the crude materialis slurried with a like quantity of ethyl acetate and heated to about78° C. to form a solution that is then held at temperature for aboutthirty minutes. The solution is cooled to about 10° C. over the courseof about two hours and seed crystals of Form A are added when thetemperature reaches about 10° C. The temperature is again reduced over afurther two hours to −10° C. during a thirty minute period thereof anamount of cyclohexane as described above is added dropwise. Thetemperature is maintained at −10° C. for two hours. The final slurry isfiltered to afford white crystals of Form B.

[0039] In a further alternate procedure, the purified material is takenup in another solvent, preferably toluene, in an amount between about 10and 20 mL per g., and heated to 75° C. to 80° C. for 30 minutes and thenallowed to cool to 20° C. and maintained for 18 hours with stirring.White crystals of Form B are recovered from the slurry by physicalseparation. The yield and purity of Form B by these procedures isconsidered very good.

[0040]FIGS. 1 through 3 are powder x-ray diffraction patterns of FormsA, B and a mixture thereof, respectively, of the subject analog. FIG. 4is a comparison of powder x-ray diffraction patterns simulated from thesingle crystal structures for Forms A and B with the actual pattern foreach. X-ray diffraction patterns were generated from a Philips Xpertwith a generator source of 44 kV and 40 mA and a CuKα filament ofλ=1.5406 Å at room temperature. In the results shown in FIGS. 1-4, aswell as in Tables 1 and 2 below which contain the data in summary form,the differences clearly establish that Forms A and B of the subjectepothilone analog possess different crystalline structures. In theTables, Peak Intensities of from 1 to 12 are classified as very weak,from 13 to 32 as weak, from 33 to 64 as average, from 65 to 87 as strongand from 88 to 100 as very strong. TABLE 1 Values for Form A PeakPosition (two theta) (CuKα λ = 1.5406 Å Relative Peak at roomtemperature) Intensity 5.69 Very weak 6.76 Very weak 8.38 Very weak11.43 Weak 12.74 Very weak 13.62 Very weak 14.35 Very weak 15.09 Veryweak 15.66 Weak 16.43 Very weak 17.16 Very weak 17.66 Very weak 18.31Weak 19.03 Weak 19.54 Average 20.57 Weak 21.06 Very strong 21.29 Weak22.31 Weak 23.02 Weak 23.66 Weak 24.18 Very weak 24.98 Weak 25.50 Weak26.23 Very weak 26.46 Very weak 27.59 Very weak 28.89 Very weak 29.58Very weak 30.32 Very weak 31.08 Very weak 31.52 Very weak

[0041] TABLE 2 Values for Form B Peak Position (two theta) (CuKα λ =1.5406 Å Relative Peak at room temperature) Intensity 6.17 Very weak10.72 Very weak 12.33 Weak 14.17 Weak 14.93 Average 15.88 Average 16.17Average 17.11 Average 17.98 Weak 19.01 Very strong 19.61 Average 20.38Average 21.55 Average 21.73 Average 22.48 Very strong 23.34 Average23.93 Average 24.78 Average 25.15 Weak 25.90 Weak 26.63 Average 27.59Very weak 28.66 Weak 29.55 Weak 30.49 Weak 31.22 Weak

[0042]FIGS. 5 through 7 are the results of Raman spectroscopy of FormsA, B and a mixture thereof, respectively, of the subject analog. Thespectra also demonstrate two distinct crystal forms, in particular thebands at 3130 cm-1 and 3115 cm-1.

[0043] Distinguishing physical characteristics of the two polymorphforms are shown in Table 3 below. Solution calorimetry was determinedusing a Thermometrics Microcalorimeter in ethanol at 25° C. Thesolubilities were likewise determined at 25° C. It is further evidentfrom certain of the data, particularly the heat of solution, that Form Ais the more stable and, therefore, Form A is preferred. TABLE 3Characteristic Form A Form B Solubility in Water 0.1254 0.1907Solubility in 3% Polysorbate 80 (Aqueous) 0.2511 0.5799 Heat of Solution20.6 9.86 kJ/mol kJ/mol

[0044] Form A and Form B of the epothilone analogs represented byformula I above can be further characterized by unit cell parametersobtained from single crystal X-ray crystallographic analysis as setforth below. A detailed account of unit cells can be found in Chapter 3of Stout & Jensen, X-Ray structure Determination: A Practical Guide,MacMillian Co., New York, N.Y. (1968). Unit Cell Unit Cell Parameters ofForm A Parameters of Form B Cell dimensions a = 14.152(6) Å a =16.675(2) Å b = 30.72(2) Å b = 28.083(4) Å c = 6.212(3) Å c = 6.054(1) ÅVolume = 2701(4) A³ Volume = 2835(1) A³ Space group P2₁2₁2₁ P2₁2₁2₁Orthorhombic Orthorhombic Molecules/unit cell 4 4 Density (calculated)1.247 1.187 (g/cm³) Melting point 182-185° C. 191-199° C. (decompostion)(decompostion)

[0045] The differences between Forms A and B of the subject epothiloneanalog are further illustrated by the solid state conformations of eachas illustrated in FIG. 8 and FIG. 9, respectively, based on thefractional atomic coordinates listed in Tables 4 through 7 below. TABLE4 Fractional Atomic Coordinates for the Epothilone Analog of Formula I:Form A Atom X Y Z U11*10e2 U22*10e2 U33*10e2 U12*10e2 U13*10e2 U23*10e2C1 0.3879(3) 0.4352(1) 0.5503(9) 60(6) 25(4) 138(8)  −2(4) 16(5) −9(4)O1 0.4055(2) 0.4300(1) 0.7435(5) 68(4) 85(4) 100(5)  6(3)  4(3)  1(3) C20.2864(3) 0.4340(1) 0.4675(7) 42(6) 64(5) 106(6)  0(4)  3(4) −5(4) C30.2696(3) 0.4210(1) 0.2325(7) 56(6) 44(5) 103(6)  −7(4)  5(4) 13(4) O30.3097(2) 0.4550(1) 0.1027(5) 71(4) 58(3) 128(4)  −6(3) 18(3)  3(3) C40.1615(3) 0.4154(1) 0.1852(7) 50(6) 63(5) 112(6) −12(4) −3(4)  7(4) C50.1289(3) 0.3732(1) 0.2895(8) 58(6) 82(6) 103(7)  −6(4) −13(5)   4(5) O50.0935(3) 0.3748(1) 0.4713(6) 135(6)  83(4) 144(5) −16(4) 39(4)  5(3) C60.1343(3) 0.3296(1) 0.1769(8) 66(6) 71(5) 118(6) −13(5) −7(4) −10(4)  C70.1503(3) 0.2921(1) 0.3353(8) 84(6) 43(5) 134(6) −27(4) −2(5) −10(5)  O70.1410(3) 0.2528(1) 0.2127(6) 127(5)  61(4) 163(5) −34(3) −17(4)  −9(3)C8 0.2449(4) 0.2936(1) 0.4540(8) 83(7) 56(5) 127(6) −26(5) −4(5)  3(5)C9 0.3284(4) 0.2824(1) 0.3072(9) 81(7) 68(5) 153(7)  −1(5) −4(5) −26(5) C10 0.4258(4) 0.2877(1) 0.4141(8) 76(7) 56(5) 166(8)  13(5) −19(5) −15(5)  C11 0.4467(3) 0.3359(1) 0.4622(8) 67(6) 61(5) 126(7)  −3(4)−19(4)  −5(5) C12 0.5220(3) 0.3426(1) 0.6294(8) 53(6) 64(5) 138(7) 16(4)  8(5) −1(5) O12 0.6171(2) 0.3288(1) 0.5612(5) 56(4) 61(3) 155(4) 15(3)  8(3)  4(3) C13 0.5983(3) 0.3746(1) 0.5991(8) 50(6) 45(5) 162(7) 3(4)  2(5) −8(5) C14 0.6099(3) 0.4053(1) 0.4113(8) 47(6) 63(5) 159(7) 2(4)  5(5)  7(5) C15 0.5568(3) 0.4477(1) 0.4538(8) 44(6) 44(5) 143(6) −4(4)  7(4) −1(4) N16 0.4552(3) 0.4426(1) 0.4005(6) 41(5) 65(4) 106(5) −3(3)  6(3) −2(3) C17 0.1482(4) 0.4138(2) −0.0603(8) 103(7)  128(7) 104(7) −29(6) −10(5)  18(5) C18 0.1043(4) 0.4539(1) 0.2734(8) 62(6)67(5) 164(7)  17(5)  9(5) 12(5) C19 0.0386(4) 0.3232(2) 0.0572(10) 92(8)115(7)   217(10) −17(6) −70(7)  −19(7)  C20 0.2404(5) 0.2630(2)0.6482(10) 145(9)  114(7)  158(8) −34(6) −20(6)  47(6) C21 0.4974(4)0.3301(2) 0.8563(9) 109(8)  92(6) 131(7)  19(5) 10(5)  8(5) C220.5935(3) 0.4860(1) 0.3281(8) 48(6) 63(5) 122(6)  6(4)  4(5) −1(5) C230.5989(4) 0.4815(2) 0.0875(8) 132(8)  78(6) 116(7)  −7(5) 12(5) −13(5) C24 0.6154(3) 0.5222(1) 0.4376(8) 59(6) 55(5) 132(6)  −6(4)  9(5)  7(5)C25 0.6392(3) 0.5656(1) 0.3573(8) 61(6) 65(5) 127(7) −12(4)  8(5)  5(5)N26 0.6786(3) 0.5941(1) 0.5076(6) 75(6) 58(5) 129(5)  −9(4)  4(4) −5(4)C27 0.6902(3) 0.6325(2) 0.4255(8) 59(6) 69(6) 128(6)  9(4)  2(5)  7(5)S28 0.6529(1) 0.6381(1) 0.1655(2) 92(2) 79(1) 163(2) −10(1) −3(1) 20(1)C29 0.6196(4) 0.5846(2) 0.1632(9) 85(7) 78(6) 161(8) −13(5) −9(6)  3(6)C30 0.7292(4) 0.6703(2) 0.5523(10) 106(8)  75(6) 186(8) −29(5) −5(6)−10(6) 

[0046] TABLE 5 Hydrogen Positions: Form A Atom X Y Z U*10E2 H210.2475(0) 0.4114(0) 0.5659(0) 4.86(0) H22 0.2576(0) 0.4663(0) 0.4871(0)4.86(0) H31 0.3056(0) 0.3905(0) 0.2005(0) 4.59(0) H3 0.3433(0) 0.4414(0)−0.0241(0) 5.55(0) H61 0.1951(0) 0.3304(0) 0.0646(0) 5.55(0) H710.0960(0) 0.2932(0) 0.4607(0) 5.80(0) H7 0.1332(0) 0.2276(0) 0.3158(0)7.23(0) H81 0.2588(0) 0.3266(0) 0.5107(0) 5.85(0) H91 0.3274(0)0.3037(0) 0.1672(0) 6.41(0) H92 0.3217(0) 0.2491(0) 0.2527(0) 6.41(0)H101 0.4802(0) 0.2743(0) 0.3130(0) 6.34(0) H102 0.4253(0) 0.2697(0)0.5663(0) 6.34(0) H111 0.4687(0) 0.3519(0) 0.3132(0) 5.60(0) H1120.3823(0) 0.3519(0) 0.5172(0) 5.60(0) H131 0.6275(0) 0.3905(0) 0.7410(0)5.60(0) H141 0.6837(0) 0.4117(0) 0.3814(0) 5.88(0) H142 0.5803(0)0.3901(0) 0.2659(0) 5.88(0) H151 0.5638(0) 0.4542(0) 0.6281(0) 5.35(0)H16 0.4353(0) 0.4447(0) 0.2429(0) 4.88(0) H171 0.1722(0) 0.4437(0)−0.1367(0) 6.90(0) H172 0.1919(0) 0.3871(0) −0.1308(0) 6.90(0) H1730.0763(0) 0.4077(0) −0.1076(0) 6.90(0) H181 0.1273(0) 0.4835(0)0.1956(0) 6.31(0) H182 0.0295(0) 0.4491(0) 0.2355(0) 6.31(0) H1830.1123(0) 0.4566(0) 0.4436(0) 6.31(0) H191 0.0370(0) 0.2923(0)−0.0226(0) 8.78(0) H192 −0.0186(0) 0.3233(0) 0.1794(0) 8.78(0) H1930.0259(0) 0.3491(0) −0.0525(0) 8.78(0) H201 0.3050(0) 0.2635(0)0.7355(0) 8.17(0) H202 0.1828(0) 0.2733(0) 0.7536(0) 8.17(0) H2030.2252(0) 0.2304(0) 0.5923(0) 8.17(0) H211 0.4260(0) 0.3415(0) 0.8951(0)6.84(0) H212 0.4998(0) 0.2955(0) 0.8754(0) 6.84(0)

[0047] TABLE 6 Fractional Atomic Coordinates for the Epothilone Analogof Formula I: Form B Atom X Y Z U11*10e2 U22*10e2 U33*10e2 U12*10e2U13*10e2 U23*10e2 C1 0.2316(2) 0.1043(2) 0.7342(8) 56(4) 74(5)  86(6) 5(4) −6(4) −16(5) O1 0.2321(2) 0.1159(1) 0.5376(5) 131(4)  88(3)  74(4)−24(3)  −13(3)   −7(3) C2 0.1812(2) 0.0623(1) 0.8106(7) 62(4) 85(5) 68(5) −7(4) −6(4) −22(5) C3 0.1535(2) 0.0622(1) 1.0506(7) 52(4) 67(4) 71(5)  1(3) −19(4)   −6(4) O3 0.2226(2) 0.0539(1) 1.1856(5) 65(3)123(4)   96(4)  7(3) −29(3)  −19(4) C4 0.0876(2) 0.0237(1) 1.0903(7)63(4) 75(4)  63(5)  5(4) −4(4) −10(4) C5 0.0096(2) 0.0415(1) 0.9838(8)57(4) 61(4)  78(5) −7(3) −2(4) −10(4) O5 −0.0132(2) 0.0252(1) 0.8117(6)100(4)  103(4)  100(4) 19(3) −38(3)  −38(4) C6 −0.0409(2) 0.0796(1)1.1023(6) 53(4) 77(4)  92(6) 14(4)  2(5) −17(5) C7 −0.0754(2) 0.1151(1)0.9373(9) 60(4) 111(4)  185(5) 40(3) 22(4) −10(4) O7 −0.1316(2)0.1434(1) 1.0606(7) 79(3) 74(5) 106(6)  4(4)  8(5) −14(5) C8 −0.0135(3)0.1468(1) 0.8213(8) 75(5) 69(4) 136(7) −10(4)  −1(5) −19(5) C9 0.0274(2)0.1817(1) 0.9812(9) 80(5) 89(5) 175(8) −21(4)  15(7) −27(6) C100.0946(3) 0.2107(2) 0.8766(10) 95(5) 98(6) 191(9) −22(5)  27(7) −48(7)C11 0.1389(3) 0.2407(2) 1.0447(11) 97(5) 64(5) 208(9) −16(5)  10(7)−28(6) C12 0.2065(3) 0.2688(2) 0.9440(11) 110(6)  98(4) 241(7) −36(3) 30(5) −77(5) O12 0.2653(2) 0.2862(1) 1.1070(8) 124(4)  82(5) 169(9)−25(5)  23(6) −38(6) C13 0.2894(3) 0.2520(2) 0.9406(10) 104(6)  102(6) 160(8) −3(5) −26(6)  −53(6) C14 0.3190(3) 0.2049(2) 1.0281(10) 117(6) 74(5) 107(6) −18(4)  −17(5)  −15(5) C15 0.3253(3) 0.1676(1) 0.8388(8)86(5) 100(4)   98(5) −26(3)  −13(4)  −19(4) N16 0.2738(2) 0.1273(1)0.8901(7) 64(4) 129(6)   66(5) −13(5)  −5(5)  10(5) C17 0.0762(3)0.0176(2) 1.3416(8) 102(6)  58(4) 113(6) 13(4) −11(5)   −9(5) C180.1109(2) −0.0244(1) 0.9909(8) 82(5) 139(7)  187(9)  1(5) 54(6)  29(7)C19 −0.1098(3) 0.0529(2) 1.2197(10) 79(5) 116(6)  123(8) 10(6) −19(6)  22(6) C20 −0.0528(3) 0.1729(2) 0.6272(9) 149(7)  86(6)  338(15) −8(6) 0(11)  21(9) C21 0.1829(4) 0.3056(2) 0.7748(15) 175(9)  80(5) 108(6)−29(4)  −5(5)  −6(5) C22 0.4128(3) 0.1527(2) 0.7991(8) 80(5) 261(11) 237(13) 28(8) 54(9)  146(11) C23 0.4521(4) 0.1784(3) 0.6109(13) 141(8) 111(6)  111(7) −5(5)  3(5)  21(6) C24 0.4477(3) 0.1216(2) 0.9319(9)88(5) 96(5) 119(7) −12(4)   2(5)  −2(6) C25 0.5303(3) 0.1032(2)0.9346(9) 76(5) 192(7)  114(6)  2(5) −6(5)  3(6) N26 0.5822(2) 0.1091(2)0.7577(8) 71(5) 165(7)  125(7) −5(6) −13(6)  −19(7) C27 0.6498(3)0.0890(2) 0.7986(10) 98(6) 128(2)  173(2) 12(1) −25(2)   0(2) S280.6565(1) 0.0612(1) 1.0487(3) 107(1)  122(6)  166(9)  4(5)  3(6)  43(7)C29 0.5605(3) 0.0785(2) 1.1053(10) 93(6) 443(17)  150(10)  45(10) 18(7) −17(12) C30 0.7206(4) 0.0891(3) 0.6410(12) 102(7) 

[0048] TABLE 7 Hydrogen Positions: Form B Atom X Y Z U*10E2 H210.1283(0) 0.0616(0) 0.7084(0) 4.86(0) H22 0.2159(0) 0.0306(0) 0.7857(0)4.86(0) H31 0.1272(0) 0.0969(0) 1.0910(0) 4.51(0) H3 0.2243(0) 0.0785(0)1.3075(0) 6.11(0) H61 −0.0043(0) 0.0983(0) 1.2199(0) 4.99(0) H71−0.1059(0) 0.0964(0) 0.8057(0) 5.69(0) H7 −0.1609(0) 0.1655(0) 0.9542(0)7.62(0) H81 0.0313(0) 0.1244(0) 0.7484(0) 5.58(0) H91 −0.0180(0)0.2062(0) 1.0453(0) 6.10(0) H92 0.0520(0) 0.1619(0) 1.1189(0) 6.10(0)H101 0.1365(0) 0.1874(0) 0.7953(0) 7.47(0) H102 0.0691(0) 0.2349(0)0.7527(0) 7.47(0) H111 0.0976(0) 0.2651(0) 1.1204(0) 7.74(0) H1120.1633(0) 0.2170(0) 1.1686(0) 7.74(0) H131 0.3308(0) 0.2613(0) 0.8107(0)7.31(0) H141 0.3779(0) 0.2094(0) 1.1016(0) 7.61(0) H142 0.2780(0)0.1920(0) 1.1530(0) 7.61(0) H151 0.3046(0) 0.1836(0) 0.6859(0) 5.74(0)H16 0.2693(0) 0.1161(0) 1.0487(0) 5.71(0) H171 0.0304(0) −0.0088(0)1.3753(0) 6.33(0) H172 0.1318(0) 0.0064(0) 1.4171(0) 6.33(0) H1730.0577(0) 0.0512(0) 1.4165(0) 6.33(0) H181 0.0633(0) −0.0501(0)1.0184(0) 5.58(0) H182 0.1192(0) −0.0207(0) 0.8122(0) 5.58(0) H1830.1655(0) −0.0370(0) 1.0628(0) 5.58(0) H191 −0.1481(0) 0.0774(0)1.3099(0) 8.04(0) H192 −0.1459(0) 0.0330(0) 1.1036(0) 8.04(0) H193−0.0849(0) 0.0274(0) 1.3402(0) 8.04(0) H201 −0.0094(0) 0.1955(0)0.5429(0) 7.89(0) H202 −0.0763(0) 0.1475(0) 0.5059(0) 7.89(0) H203−0.1024(0) 0.1951(0) 0.6816(0) 7.89(0) H211 0.1596(0) 0.2886(0)0.6259(0) 11.47(0) H212 0.1382(0) 0.3292(0) 0.8404(0) 11.47(0) H2130.2355(0) 0.3265(0) 0.7267(0) 11.47(0) H231 0.5051(0) 0.1602(0)1.0559(0) 6.57(0) H291 0.5291(0) 0.0702(0) 1.2584(0) 7.73(0) H3010.7003(0) 0.0920(0) 0.4744(0) 13.05(0) H302 0.7623(0) 0.1165(0)0.6811(0) 13.05(0) H303 0.7525(0) 0.0542(0) 0.6572(0) 13.05(0)

[0049] Based on the foregoing data, it is concluded that Forms A and Bare unique crystalline entities.

[0050] The following non-limiting examples serve to illustrate thepractice of the invention.

EXAMPLE 1

[0051] [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione.

[0052] To a jacketed 125 mL round bottom flask, fitted with a mechanicalstirrer, there was combined epothilone-B (5.08 g), tetrabutylammoniumazide (Bu₄NN₃) (3.55 g, 1.25 equivalents), ammonium chloride (1.07 g, 2eq), water (1.8 ml, 10 equivalents), tetrahydrofuran (THF) (15 ml), andN,N-dimethylformamide (DMF) (15 ml). The mixture was inerted by spargingnitrogen subsurface for 15 minutes. In a second flask was chargedtetrahydrofuran (70 ml), followed by trimethylphosphine (PMe₃) (1.56 ml,1.5 equivalents), thentris(dibenzilideneacetone)-dipalladium(0)-chloroform adduct(Pd₂(dba)₃CHCl₃)(0.259 g, 0.025 equivalents). The catalyst mixture wasstirred for 20 minutes at ambient temperature, then added to theepothilone-B mixture. The combined mixture was stirred for 4.5 hours at30° C. The completed reaction mixture was then filtered to remove solidammonium chloride (NH₄Cl). The filtrate contained (βS, εR, ζS, ηS, 2R,3S)-3-[(2S, 3E)-2-amino -3-methyl-4-(2-methyl-4-thiazolyl)-3-butenyl]-β,ζ-dihydroxy-γ, γ, ε, η, 2-pentamethyl-6-oxooxiraneundecanoic acid,tetrabutylammonium salt (1:1) with a HPLC area of 94.1%.

[0053] In a 500 mL flask there was combined1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI)(3.82 g, 2 equivalents), 1-hydroxy-7-benzotriazole hydrate (HOBt) (1.68g, 1.1 equivalents), potassium carbonate (1.38 g, 1 equivalent), N,N-dimethylformamide (DMF) (40 ml) and tetrahydrofuran (THF) (160 ml).The mixture was warmed to 35° C. and the filtrate from above was addedthereto, dropwise over a period of three hours. This mixture was thenstirred for an additional 1 hour at 35° C. Vacuum distillation was thenapplied to the reaction mixture to reduce the volume thereof to about 80mL. The resulting solution was partitioned between 100 mL of ethylacetate and 100 mL of water. The aqueous layer was then back-extractedwith 100 ml ethyl acetate. The combined organic layers were extractedwith 50 ml water and then 20 mL brine. The resulting product solutionwas filtered through a Zeta Plus® pad and then stripped to an oil. Thecrude oil was dissolved in dichloromethane (20 mL) and washed with waterto remove final traces of synthesis solvents and stripped to a solid.The crude solid was chromatographed on silica gel 60 (35 ml silica pergram of theoretical product) with an eluent comprised of 88%dichloromethane (CH₂Cl₂), 10%-30% ethyl acetate (EtOAc) and 2%triethylamine (Et₃N). The fractions were analyzed by HPLC, the purest ofwhich were combined and stripped to give the purified solid. Theresulting solid, approx. 2 g, was slurried in ethyl acetate (32 ml) for40 minutes at 75° C., then cyclohexane (C₆H₁₂) (16 ml) was slowly added,and the mixture cooled to 5° C. The purified solid was collected onfilter paper, washed with cold ethyl acetate/cyclohexane, and dried. Theyield was 1.72 g (38% yield) of the white solid product,[1S-[1R*,3R*(E),7R*, 10S*, 11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione,with a HPLC area of 99.2%.

EXAMPLE 2

[0054] [1S-[1R*,3R*(E),7R*,10S*, 11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, Form A.

[0055] A 250 mL three-neck flask was charged with 0.61 g of the titlecompound that had been purified (silica gel pad filtration withEtOAc/hexane/Et₃N as the eluent, HPLC area of 96.88) and ethyl acetate(28 mL, 46 ml/l g). The resultant slurry was heated to 75° C. All ofsolids were dissolved after the slurry was stirred at 75° C. for 60minutes. The afforded solution was cooled from 75° C. to 50° C. over 120minutes, seed crystals of Form A being added at 60° C. Crystals appearedat 55° C. The temperature was thereafter cooled to 20° C. over 120minutes, while cyclohexane (35 mL, 57 mL/1 g) was added dropwise to themixture over a period of 60 minutes. The obtained slurry was cooled to−10° C. over 120 minutes, and maintained for an additional 60 minutes.The slurry was filtered and the afforded white crystals were dried togive 0.514 g of the title compound, Form A, in 84.3% yield with an HPLCarea of 99.4.

[0056] Form A—Alternate Procedure

[0057] A 250 mL three-neck flask was charged with 0.51 g of the titlecompound that had been purified (silica gel pad filtration withEtOAc/hexane/Et₃N as the eluent, HPLC area of 96) and ethyl acetate (8.5mL, 16.7 ml/1 g). The resultant slurry was heated to 80° C. The affordedsolution was cooled from 80° C. to 70° C. over 60 minutes, seed crystalsof Form A being added at 70° C. The temperature was thereafter cooled to30° C. over 180 minutes. Crystals appeared at 65° C. The solution wasfurther cooled to −10° C. over 180 minutes, while cyclohexane (10.2 mL,20 mL/1 g) was added dropwise to the mixture over a period of 30minutes. The obtained slurry was cooled maintained for an additional 60minutes. The slurry was filtered and the afforded white crystals weredried to give 0.43 g of the title compound, Form A, in 84.3% yield withan HPLC area of 99.7.

[0058] Form A—Alternate Procedure

[0059] A 500 mL three-neck flask was charged with 18.3 g of a mixture ofForms A and B that had been purified (silica gel pad filtration withEtOAc/dichloromethane/Et₃N as the eluent, HPLC area of 99) and ethylacetate (183 mL, 10 ml/1 g). The resultant slurry was heated to 75° C.,seed crystals of Form A were added and the temperature was maintainedfor 30 minutes. Cyclohexane (90.2 mL, 5 mL/1 g) was added dropwise tothe mixture keeping the temperature at 70° C. After completion of theaddition, the temperature was lowered to 20° C. and the mixturemaintained with stirring for a further 18 hours. The temperature wasthereafter lowered to 5° C. and maintain for 5 hours. The slurry wasfiltered and the afforded white crystals were dried to give 16.1 g ofthe title compound, Form A, in 88% yield with an HPLC area of 99.49.

EXAMPLE 3

[0060] [1S-[1R*,3R*(E),7R*, 10S*, 1R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, Form B.

[0061] A 250 mL three-neck flask was charged with 0.108 g of the titlecompound that had not been purified as in Example 2, N,N-dimethylformamide (0.0216 g) and ethyl acetate (5 mL, 46 ml/1 g). The resultantslurry was heated to 80° C. and stirred for 30 minutes to dissolve allsolids. The afforded solution was cooled from 80° C. to 30° C. over 120minutes, crystals appearing at 38° C. Cyclohexane (7.5 mL, 69.5 mL/1 g)was added dropwise to the mixture over a period of 30 minutes while thetemperature was cooled to −10° C. over 60 minutes, and maintained for anadditional 120 minutes. The slurry was filtered and the afforded whitecrystals were dried to give 0.082 g of the title compound, Form B, in76% yield with an HPLC area of 99.6.

[0062] Form—Alternate Procedure

[0063] A 250 mL three-neck flask was charged with 0.458 g of the titlecompound that had not been purified as in Example 2 and contained about6% of N,N-dimethyl formamide and ethyl acetate (10 mL, 21.8 ml/1 g). Theresultant slurry was heated to 78° C. and stirred for 30 minutes todissolve all solids. The afforded solution was cooled from 78° C. to 10°C. over 120 minutes. Seed crystals of Form A were added at 10° C.Cyclohexane (20 mL, 43.7 mL/1 g) was added dropwise to the mixture overa period of 60 minutes while the temperature was cooled to −10° C. over120 minutes, and maintained for an additional 120 minutes. The slurrywas filtered and the afforded white crystals were dried to give 0.315 gof the title compound, Form B, in 68.8% yield with an HPLC area of 98.2.

[0064] Form B—Alternate Procedure

[0065] A 5-mL Wheaton bottle was charged with 250 mg of the titlecompound that had not been purified as in Example 2 and toluene (3.75mL, 15 mL/g.) and the resultant slurry heated to 75° C. and held for 30minutes. The resultant suspension was allowed to cool to 20° C. andmaintained at that temperature for 18 hours with stirring. The slurrywas filtered and the afforded white crystals dried to give 150 mg. ofthe title compound, Form B, in 60% yield with an HPLC area of 99.2

We claim:
 1. A crystalline polymorph of an epothilone analog representedby the formula

comprising Form A characterized by: unit cell parameters approximatelyequal to the following: Cell dimensions a = 14.152(6) Å b = 30.72(2) Å c= 6.212(3) Å Volume = 2701(4) A³ Space group P2₁2₁2₁ OrthorhombicMolecules/unit cell 4 Density (calculated) (g/cm³) 1.247 Melting point182-185° C. (decomposition); and

characteristic peaks in the powder x-ray diffraction pattern at valuesof two theta (CuKα λ=1.5406 Å at 22° C.): 5.69, 6.76, 8.38, 11.43,12.74, 13.62, 14.35, 15.09, 15.66, 16.43, 17.16, 17.66, 18.31, 19.03,19.54, 20.57, 21.06, 21.29, 22.31, 23.02, 23.66, 24.18, 14.98, 25.50,26.23, 26.23, 26.46, 27.59, 28.89, 29.58, 30.32, 31.08 and 31.52; orForm B is characterized by: unit cell parameters approximately equal tothe following: Cell dimensions a = 16.675(2) Å b = 28.083(4) Å c =6.054(1) Å Volume = 2835(1) A³ Space group P2₁2₁2₁ OrthorhombicMolecules/unit cell 4 Density (calculated) (g/cm³) 1.187 Melting point191-199° C. decomposition; and

characteristic peaks in the powder x-ray diffraction pattern at valuesof two theta (CuKα λ=1.5406 Å at 22° C.): 6.17, 10.72, 12.33, 14.17,14.93, 15.88, 16.17, 17.11, 17.98, 19.01, 19.61, 20.38, 21.55, 21.73,22.48, 23.34, 23.93, 24.78, 25.15, 25.90, 26.63, 27.59, 28.66, 29.55,30.49 and 31.22.
 2. A crystalline polymorph of an epothilone analogrepresented by the formula

comprising Form A characterized by powder x-ray diffractionsubstantially as shown in FIG. 1 and a Raman spectrum substantially asshown in FIG. 5; or Form B characterized by powder x-ray diffractionsubstantially as shown in FIG. 2 and a Raman spectrum substantially asshown in FIG.
 6. 3. A crystalline polymorph of an epothilone analogrepresented by the formula

comprising Form A characterized by a solubility in water of 0.1254, asolubility in a 3% aqueous solution of polysorbate 80 of 0.2511, amelting point with decomposition between 182-185° C. and a heat ofsolution of 20.6 kJ/mol; or Form B characterized by a solubility inwater of 0.1907, a solubility in a 3% aqueous solution of polysorbate 80of 0.5799, a melting point with decomposition between 191-199° C. and aheat of solution of 9.86 kJ/mol.
 4. A crystalline polymorph inaccordance with claim 1 wherein said polymorph is Form A.
 5. Acrystalline polymorph in accordance with claim 2 wherein said polymorphis Form A.
 6. A crystalline polymorph in accordance with claim 3 whereinsaid polymorph is Form A.
 7. A crystalline polymorph in accordance withclaim 1 wherein said polymorph is Form B.
 8. A crystalline polymorph inaccordance with claim 2 wherein said polymorph is Form B.
 9. Acrystalline polymorph in accordance with claim 3 wherein said polymorphis Form B.
 10. A crystalline material comprising a mixture of Form A andForm B in accordance with claim
 1. 11. A crystalline material comprisinga mixture of Form A and Form B in accordance with claim
 2. 12. Acrystalline material comprising a mixture of Form A and Form B inaccordance with claim
 3. 13. A process for producing a crystallinepolymorph that is Form A of the epothilone analog represented by formulaI in claim 1 comprising heating a slurry of said analog represented byformula I in from about 8 to about 16 mL of ethyl acetate per gram ofsaid analog to about 75° C. maintaining the temperature for about onehour, adding an amount of cyclohexane in a ratio to the amount of ethylacetate of from about 1:2 to about 2:2, allowing the mixture to cool toambient temperature, maintain the mixture with stirring from about 12 to96 hours, further cooling it to about 5° C. over about two hours andrecovering the crystalline Form A therefrom.
 14. A process in accordancewith claim 13 wherein the amount of cyclohexane added is in a 1:2 ratioto the amount of ethyl acetate utilized to form said slurry.
 15. Aprocess in accordance with claim 13 wherein said slurry of said analogrepresented by formula I in ethyl acetate is heated to about 75° C. seedcrystals are added thereto and the mixture is maintained for about 30minutes after which said amount of cyclohexane is added thereto whilemaintaining the mixture at about 70° C., cooling the mixture to ambienttemperature, maintain the mixture with stirring for about 18 hours,further cooling it to about 5° C. over about two hours and recoveringthe crystalline Form A therefrom.
 16. A process in accordance with claim13 wherein said slurry of said analog represented by formula I in ethylacetate is heated to about 75° C. for at least an hour until a solutionis formed, cooling said solution to about 50° C. over about two hours,adding said seed crystals thereto when the temperature reaches about 60°C., cooling the solution to about 30° C. over about three hours, furtherreducing the temperature of the solution to −10° C. over about threehours during one hour of which said amount of cyclohexane is addedthereto dropwise, maintaining the resultant mixture at −10° C. for aboutone hour and recovering the crystalline Form A therefrom.
 17. A processfor producing a crystalline polymorph that is Form B of the epothiloneanalog represented by formula I in claim 1 comprising heating a slurryof said analog represented by formula I in from about 40 to about 50 mLof ethyl acetate per gram of said analog to about 75° C. to 80° C.,maintaining the temperature for about one hour thereby forming asolution, maintaining the solution at temperature for about 30 minutes,cooling the solution to about 30° C. over about two hours, furtherreducing the temperature of the solution to −10° C. over about one hourduring which an amount of cyclohexane in a ratio to the amount of ethylacetate of from about 1:2 to about 2:2 is added thereto dropwise over aperiod of about thirty minutes, maintaining the resultant mixture at - I0° C. for about two hours and recovering the crystalline Form Btherefrom.
 18. A process in accordance with claim 17 wherein said slurryof said analog represented by formula I in ethyl acetate is heated toabout 78° C. thereby forming a solution, cooling the solution to about10° C. over about two hours, adding seed crystals when the temperaturereaches 10° C., further reducing the temperature of the solution to −10°C. over about two hours during which said amount of cyclohexane is addedthereto dropwise over a period of about thirty minutes, maintaining theresultant mixture at −10° C. for about two hours and recovering thecrystalline Form B therefrom.
 19. A process for producing a crystallinepolymorph that is Form B of the epothilone analog represented by formulaI in claim 1 comprising heating a slurry of said analog represented byformula I in from about 10 to about 20 mL of toluene per gram of saidanalog to about 75° C. to 80° C., maintaining the temperature for about30 minutes, cooling the mixture to about 20° C., maintaining thetemperature for about 18 hours with stirring and recovering thecrystalline Form B therefrom.
 20. A pharmaceutical composition whichcomprises as an active ingredient an effective amount a crystallinepolymorph as claimed in claim 1 and one or more pharmaceuticallyacceptable carriers, excipients or diluents thereof.
 21. Apharmaceutical composition which comprises as an active ingredient aneffective amount a crystalline polymorph as claimed in claim 2 and oneor more pharmaceutically acceptable carriers, excipients or diluentsthereof.
 22. A pharmaceutical composition which comprises as an activeingredient an effective amount a crystalline polymorph as claimed inclaim 3 and one or more pharmaceutically acceptable carriers, excipientsor diluents thereof.
 23. A pharmaceutical composition in accordance withclaim 20 wherein said crystalline polymorph is Form A.
 24. Apharmaceutical composition in accordance with claim 20 wherein saidcrystalline polymorph is Form B.
 25. A pharmaceutical composition inaccordance with claim 20 wherein said crystalline polymorph is a mixtureof Form A and Form B.
 26. A method for treating cancer or otherproliferative diseases which comprises administering to a mammal in needthereof an effective amount of a crystalline polymorph as claimed inclaim
 1. 27. A method for treating cancer or other proliferativediseases which comprises administering to a mammal in need thereof aneffective amount of a crystalline polymorph as claimed in claim
 2. 28. Amethod for treating cancer or other proliferative diseases whichcomprises administering to a mammal in need thereof an effective amountof a crystalline polymorph as claimed in claim
 3. 29. A method inaccordance with claim 26 wherein said crystalline polymorph is Form A.30. A method in accordance with claim 26 wherein said crystallinepolymorph is Form B.
 31. A method in accordance with claim 26 whereinsaid crystalline polymorph is administered parenterally.